Biliary excretion is a major route of elimination of both exogenous and endogenous compounds. Cellular mechanisms that regulate the hepatic uptake and binary excretion of non-metabolized xenobiotics have been characterized in our laboratory during the past several years. In comparison, the regulation of the hepatobiliary disposition of metabolized compounds is not well understood. Most compounds undergo phase II drug metabolism before being excreted into bile. One of these phase II biotransformation processes is sulfation. Sulfation is a low-capacity conjugation system suggested to be limited by the availability of adenosine 3'-phosphate 5'-phosphosulfate (PAPS). However, due to the lack of an adequate method to I quantitate PAPS in tissues, this hypothesis could not be tested. Recently, we developed such a method and 1 demonstrated that the concentration of PAPS in liver as well as sulfate in plasma is decreased after administration of drugs that are sulfated. Thus, we propose a number of experiments to determine the availability and source of sulfur necessary for the synthesis of PAPS. Understanding the regulation of PAPS synthesis is extremely important because sulfation is a major detoxification system. Thus, the augmentation of this pathway might be useful in preventing chemical toxicity. Another important phase II !drug metabolism process is glucuronidation. There were thought to be three classes of glucuronosyltransferase inducers exemplified by 3-methylcholanthrene, phenobarbital, and clofibrate. We have recently demonstrated that pregnenolone-16 alpha-carbonitrile induces another class of glucuronosyltransferase. The first class of inducers produce hypothyroxinemia. Thyroxine is mainly deactivated by glucuronidation. Therefore, we propose to determine whether all four classes of iglucuronosyltransferase inducers produce hypothyroxinemia, and more importantly, the mechanism(s) by which the inducers produce this effect. We will first determine whether the hypothyroxinemia is a peripheral effect by removing the thyroid and administering thyroxine by a minipump and determining whether these chemicals lower plasma thyroxine levels. If the plasma levels decrease, sequential experiments will be performed to determine whether this is due to an increase in urinary or fecal excretion of thyroxine metabolites and the chemical form of these metabolites. If the biliary excretion of metabolites is altered and depending on if and what metabolites are increased, we will then examine the mechanism for the alteration, such as an increase in UDP-glucuronosyltransferase or UDP-glucuronic acid, and 5'-deiodinase. We will also determine how these chemicals affect the uptake of thyroxine into the liver as our previous work has indicated that some microsomal enzyme inducers enhance the elimination of chemicals by increasing the number of carrier-mediated transport processes for hepatic uptake. These studies are significant because they will provide new concepts concerning chemical-induced alteration of thyroid function, not only for one chemical but potentially for many chemicals.